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早期干预ERK在脊髓的激活可阻断外周神经损伤引起的神经病理性疼痛的发生

韩梅, 黄如一, 杜逸旻, 赵志奇, 张玉秋^*

复旦大学神经生物学研究所，脑科学研究院，医学神经生物学国家重点实验室，上海 200032；复旦大学生命科学学院，上海 200433

摘要

本文采用大鼠坐骨神经慢性压迫损伤引起的神经病理痛模型，研究脊髓背角细胞外信号调节激酶(extracellular signalregulated kinase, ERK)在外周神经损伤引起的神经病理疼痛发生中的作用。结果显示，单侧坐骨神经压迫性损伤后1天，大鼠损伤侧脊髓背角ERK的磷酸化(激活)水平显著上调，其下游转录因子cAMP 反应原件结合蛋白(cAMP response element binding protein, CREB)在双侧脊髓背角的激活水平也同时上调，而此时由神经损伤引起的痛觉敏化行为尚未出现。神经损伤之前和损伤后早期鞘内给予促分裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase, MEK)的抑制剂U0126，可阻断和延迟坐骨神经损伤引起的触诱发痛和热痛觉过敏行为的发生。这些结果提示，脊髓背角ERK-CREB信号的激活参与外周神经损伤引起的神经病理疼痛的发生，对该信号通路的早期干预可能是控制神经病理性疼痛的重要手段。

关键词： 触诱发痛; 痛觉过敏; ERK-CREB信号通路; 早期干预; 脊髓; 大鼠

分类号：Q42

Early intervention of ERK activation in the spinal cord can block initiation of peripheral nerve injury-induced neuropathic pain in rats

HAN Mei, HUANG Ru-Yi, DU Yi-Min, ZHAO Zhi-Qi, ZHANG Yu-Qiu^*

Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China； Department of Life Science, Fudan University, Shanghai 200433, China.

Abstract

The present study is to investigate whether the extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) signaling pathway contributes to the initiation of chronic constriction injury (CCI)-induced neuropathic pain in rats. Mechanical allodynia was assessed by measuring the hindpaw withdrawal threshold in response to a calibrated series of von Frey hairs. Thermal hyperalgesia was assessed by measuring the latency of paw withdrawal in response to a radiant heat source. The expressions of phosphor-ERK (pERK) and phosphor-CREB (pCREB) were examined using Western blot analysis and immunohistochemistry. An early robust increase in the expression of pERK on the spinal cords ipsilateral to injury was observed on day 1 after CCI, when the CCI-induced behavioral hypersensitivity had not developed yet. Moreover, the upregulation of pERK expression in ipsilateral spinal cord was associated with the increase in pCREB expression in bilateral spinal cord. Intrathecal administration of mitogen-activated protein kinase kinase (MEK) inhibitor U0126 before CCI can efficiently block and delay the CCI-induced mechanical allodynia and thermal hyperalgesia. These data suggest that activation of ERK and CREB in the spinal cord contributes to the initiation of peripheral nerve injury-induced pain hypersensitivity, and an early intervention strategy should be proposed.

Key words: allodynia; hyperalgesia; ERK-CREB signaling pathway; early intervention; spinal cord; rats

收稿日期：2011-01-05　　录用日期：2011-04-06

通讯作者：张玉秋　　E-mail: yuqiuzhang@fudan.edu.cn.

引用本文：

韩梅, 黄如一, 杜逸旻, 赵志奇, 张玉秋. 早期干预ERK在脊髓的激活可阻断外周神经损伤引起的神经病理性疼痛的发生[J]. 生理学报 2011; 63 (2): 106-114.

HAN Mei, HUANG Ru-Yi, DU Yi-Min, ZHAO Zhi-Qi, ZHANG Yu-Qiu. Early intervention of ERK activation in the spinal cord can block initiation of peripheral nerve injury-induced neuropathic pain in rats. Acta Physiol Sin 2011; 63 (2): 106-114 (in Chinese with English abstract).